Regulation of the number of insulin receptors on the cell surface plays a critical role in determining insulin sensitivity. Previously, we have demonstrated that the insulin receptor is regulated at the transcriptional level by glucocorticoids. In order to study the mechanism of transcriptional regulation of the insulin receptor gene, we have cloned the 5' end of the human insulin receptor gene. We have begun to characterize the promoter and find it has many features of a "housekeeping gene". The 51 flanking region of the gene has been sequenced and is extremely G-C rich. Using primer extension, multiple transcription starts sites have been identified. Using an expression vector, we have localized the promoter activity to a 70 bp region by deletion analysis. We have localized a weak enhancer upstream of the promoter. In addition, this promoter demonstrates the unusual property of functioning equally well in either orientation. Further studies to identify sequences responsible for the transcriptional regulation are underway.